This application is the national stage of PCT FR 09/03255 filed Dec. 22, 1999, now WO 00/040526.
A subject matter of the present invention is a process for the preparation of xcex2-phosphorated nitroxide radicals of formula: 
in which R1, R2, R3, R4 and R5 will be defined subsequently. These compounds are used in particular as regulators of radical polymerization.
These compounds can be obtained in particular by the oxidation of N-alkylaminophosphonates of formula: 
The N-alkylaminophosphonates (II) can be obtained in a known way by reacting a carbonyl compound R1R2C(O), a primary amine R3NH2 and a phosphorus compound HP(O)R4R5 having a mobile hydrogen according to a Mannich-type reaction: 
A process is disclosed in international patent application WO 96/24620 which consists in reacting, in a first stage, a carbonyl compound R1R2C(O) with a primary amine R3NH2 according to a carbonyl compound/primary amine molar ratio substantially equal to 1 and then, in a second stage, in adding, to the compound obtained in the first stage, a phosphorus compound HP(O)R4R5 according to a phosphorus compound/product obtained in the first stage molar ratio ranging from 1.5 to 2.5, indeed even more. There are several disadvantages to this way of proceeding.
Thus, the water formed in the first stage during the reaction of the carbonyl compound with the primary amine which results in the formation of an imine according to the scheme:
 greater than Cxe2x95x90O+xe2x80x94NH2xe2x86x92 greater than Cxe2x95x90Nxe2x80x94+H2O
is not removed before the addition of the phosphorus compound, which may be of such a nature as to result in a possible hydrolysis of said phosphorus compound, in particular when the latter is a phosphite.
In addition, the use of a very large excess of phosphorus compound (150% to 250%, indeed even more) with respect to the compound obtained in the first stage (imine) is prohibitory for an industrial process.
Furthermore, this excess, in addition to the fact of the difficulties in removing it, is of such a nature as to generate numerous impurities by reaction with, in particular, the unconverted carbonyl compound to result in hydroxyphosphonates ( greater than C(OH)xe2x80x94P(O) less than ) in the case where the phosphorus compound used is a phosphite. This excess of phosphorus compound can also result in the formation of heavy products resulting from the reaction between (II), the carbonyl compound and the excess phosphorus compound HP(O)R4R5.
All these impurities liable to be present in the crude product (II) make the purification of the N-alkylaminophosphonate (II) difficult and consequently render its subsequent use difficult.
The xcex2-phosphorated nitroxide (I) can be obtained by oxidation of the N-alkylaminophosphonate (II) by replacing the hydrogen of  greater than Nxe2x80x94H with an oxygen atom.
This oxidation can be carried out according to various techniques known to a person skilled in the art. A few appropriate techniques are listed below in a nonexhaustive fashion:
reaction of a secondary amine with aqueous hydrogen peroxide solution in the presence of a solid catalyst (titanium silicalite), the principle of which is disclosed in patent U.S. Pat. No. 5,218,116;
reaction of a secondary amine with a dioxirane or its carbonyl precursors in combination with oxone(copyright), the technique of which is disclosed in patent U.S. Pat. No. 5,087,752,
reaction of a secondary amine with metachloroperbenzoic acid, according to a protocol described in the Journal of the American Chemical Society, 1967, 89 (12), pages 3055-3056.
According to international application WO 96/24620, diethyl 2,2-dimethyl-1-(1,1-dimethylethylamino)propylphosphonate could only be efficiently oxidized by means of meta-chloroperbenzoic acid (mCPBA) according to a protocol which consists in introducing the mCPBA, in solution in CH2Cl2, into a CH2Cl2 solution of the abovementioned aminophosphonate. The xcex2-phosphorated nitroxide obtained is purified by passing through a column of silica gel, which involves the use of a large volume of elution solvent.
This way of operating can only be applied to the preparation of small amounts of (I). In addition, the analysis of this product by HPLC has shown that this technique results in nitroxides with a purity of less than 80%.
In order to improve the process for the oxidation of the aminophosphonate (II) by mCPBA, the assignee of the present application has carried out the preliminary drying of the technical mCPBA, on the one hand, and optimized the mCPBA/aminophosphonate molar ratio, on the other hand.
Although a satisfactory yield of xcex2-phosphorated nitroxide is obtained, this way of operating produces amounts of effluents (metachlorobenzoic acid salt) which are difficult to remove.
Furthermore, even the optimized use of mCPBA does not make possible viable translocation to the industrial scale.
The applicant has found that, by using nonhalogenated organic peracids in a water/organic solvent two-phase medium with an aqueous phase buffered at a pH ranging from 5 to 12, it can oxidize aminophosphonates (II) to xcex2-phosphorated nitroxides (I) while significantly reducing the manufacturing costs and while generating effluents which can be easily removed.
A subject matter of the present invention is thus a process for the manufacture of compounds of general formula: 
in which R1 and R2, which are identical or different, represent a hydrogen atom, a linear, branched or cyclic alkyl radical having a number of carbon atoms ranging from 1 to 10, an aryl radical, or an aralkyl radical having a number of carbon atoms ranging from 1 to 10, or else R1 and R2 are connected to one another so as to form a ring which includes the carbon atom carrying said R1 and R2 said ring having a number of carbon atoms, including the carbon carrying the R1 and R2 radicals, ranging from 3 to 8; R3 represents a linear or branched and saturated or unsaturated hydrocarbonaceous radical which can comprise at least one ring, said radical having a number of carbon atoms ranging from 1 to 30; and R4 and R5, which are identical or different, represent a linear or branched alkyl radical having a number of carbon atoms ranging from 1 to 20 or a cycloalkyl, aryl, alkoxyl, aryloxyl, aralkyloxyl, perfluoroalkyl, aralkyl, dialkyl- or diarylamino, alkylarylamino or thioalkyl radical, or else R4 and R5 are connected to one another so as to form a ring which includes the phosphorus atom, said heterocycle having a number of carbon atoms ranging from 2 to 4 and being able in addition to comprise one or more oxygen, sulfur or nitrogen atoms;
said process consisting in oxidizing an aminophosphonate of formula 
obtained by reaction of a carbonyl compound R1R2C(O), of a primary amine R3NH2 and of a phosphorus compound HP(O)R4R5, R1, R2, R3, R4 and R5 having the meanings given above; said process being characterized in that it consists first in preparing and optionally in isolating the compound II and then subsequently in oxidizing it by carrying out the following (successive) stages:
a) a carbonyl compound R1R2C(O) is reacted with a primary amine R3NH2 according to an R1R2C(O)/R3NH2 molar ratio of between 0.8 and 1.5 and preferably between 0.9 and 1.1 at a temperature of between 0xc2x0 C. and 120xc2x0 C. and a pressure ranging from 1 to 10 bar; then the water formed is removed from the reaction medium;
b) the compound obtained in a) is reacted with a phosphorus compound HP(O)R4R5 used according to an HP(O)R4R5 /compound a) molar ratio at most equal to 1.5 and preferably of between 1 and 1.5 at a temperature of between 0xc2x0 C. and 120xc2x0 C.;
c) an acidic treatment of the reaction medium obtained in b) is carried out, an organic solvent is subsequently added, separation by settling is carried out, the aqueous phase is recovered and then a basic treatment of said aqueous phase is carried out;
d) the aminophosphonate is extracted by means of an organic solvent identical to that used previously in c);
e) said solvent is then completely removed and said aminophosphorate (II) is isolated and is oxidized to xcex2-phosphorated nitroxide according to the following stages:
a1) the aminophosphonate (II) obtained in e) is dissolved in a water-immiscible organic solvent, then;
b1) subsequently, an amount of non-halogenated organic peracid, according to a peracid/aminophosphonate (II) molar ratio ranging from 1.5 to 2.5, and a sufficient amount of a basic aqueous solution of an alkali metal carbonate or hydrogencarbonate or of an alkaline earth metal carbonate or hydrogencarbonate or alternatively of an ammonia solution to produce a pH ranging from 5 to 12 and preferably ranging from 6 to 9 are simultaneously added with vigorous stirring, at a temperature of between xe2x88x9210xc2x0 C. and +40xc2x0 C. and preferably of between xe2x88x925xc2x0 C. and +30xc2x0 C., to the medium thus obtained, until the aminophosphonate (II) has been completely converted;
c1) the organic phase is then recovered by simple separation by settling and the xcex2-phosphorated nitroxide is isolated by evaporation of the organic solvent under reduced pressure.
The purity of the xcex2-phosphorated nitroxide obtained can be improved by flash distillation under reduced pressure or by low temperature crystallization.
According to an alternative form of the process of the present invention, it is possible not to isolate the aminophosphonate (II) and to carry out the oxidation on the aqueous phase obtained in c), which comprises the aminophosphonate hydrochloride.
Should that arise, the procedure is thus carried out in the following way:
after having carried out the acidic treatment of the reaction medium obtained in b) and then added a water-immiscible organic solvent, the aqueous phase is separated by settling, an organic solvent is added to the aqueous phase and then stages b1) and c1) as described above are carried out.
Mention will be made, by way of illustration of carbonyl compounds R1R2C(O) which can be used according to the present invention, of trimethylacetaldehyde (pivalaldehyde), isobutyraldehyde, cyclohexanecarboxyaldehyde, diethyl ketone, dibutyl ketone, methyl ethyl ketone, cyclohexanone, 4-tert-butylcyclohexanone or xcex1-tetralone.
Mention will be made, by way of illustration of primary amines R3xe2x80x94NH2 which can be used according to the present invention, of methylamine, ethylamine, propylamine, isopropylamine, tert-butylamine, diphenylmethylamine, triphenylmethylamine, aniline, xcex1-naphthylamine, benzylamine, 1-phenylethylamine, cyclohexylamine or cyclopentylamine.
Use will preferably be made of tert-butylamine, isopropylamine, diphenylmethylamine, 1-phenylethylamine or cyclohexylamine.
The reaction between the carbonyl compound R1R2C(O) and the amine R3NH2 (stage a) is carried out with vigorous stirring at a temperature of between 0xc2x0 C. and 120xc2x0 C. and preferably at a temperature of between 0xc2x0 C. and 60xc2x0 C. The reaction is generally carried out at a pressure of between 1 bar and 10 bar, preferably at atmospheric pressure, and under an inert gas atmosphere, such as nitrogen or argon. The reaction time can vary within wide limits. It depends on the reactivity of the amine employed. The complete conversion of the carbonyl compound R1R2C(O) can be confirmed by chromatographic (GC) analysis.
On completion of the reaction, stirring is halted and the reaction medium is allowed to separate by settling. Separation by settling is generally rapid. The aqueous phase, consisting virtually entirely of the water formed during the reaction between the carbonyl compound and the primary amine which results in the imine (III), according to the scheme: 
is subsequently removed.
The removal of the water can be completed by the addition of a dehydrating agent, such as a molecular sieve, to the phase which has been separated by settling or alternatively azeotropic distillation can be carried out.
The imine (III) obtained in stage a) is reacted with a compound HP(O)R4R5 (stage b)).
Mention will be made, by way of illustration of phosphorus compounds HP(O)R4R5 which can be used according to the present invention, of dimethyl phosphite, diethyl phosphite, n-propyl phosphite, dibenzyl phosphite, diisopropyl phosphite, di(n-dodecyl)phosphite; diphenylphosphine oxide or dibenzylphosphine oxide.
The reaction between the phosphorus compound HP(O)R4R5 and the imine (III) obtained in stage a) is carried out with vigorous stirring at a temperature of between 0xc2x0 C. and 120xc2x0 C. and preferably at a temperature of between 10xc2x0 C. and 80xc2x0 C. As in stage a), the reaction is carried out under an inert gas atmosphere and preferably at atmospheric pressure.
Use is made of a molar excess of phosphorus compound HP(O)R4R5 with respect to the imine obtained in stage a) at most equal to 50% and preferably of an excess which is as low as possible, indeed even zero phosphorus compound/imine (III) molar ratio equal to 1).
The reaction medium is kept stirred for a time which can vary within wide limits; this time is preferably at most equal to 25 hours.
The reaction medium is subsequently acidified (stage c)) with an aqueous hydrochloric acid solution.
The concentration by weight of HCl is at most equal to 20% and preferably between 5% and 15%. This acidification is preferably carried out at a temperature of between 0xc2x0 C. and 20xc2x0 C. and preferably at a temperature in the region of 10xc2x0 C.
When the pH of the reaction medium is less than 3, a first extraction is carried out which consists in removing the organic impurities and unconverted reactants with an organic solvent which is a good solvent of the impurities. Methylene chloride (CH2Cl2) will advantageously be used.
Subsequently, the acidic aqueous phase (comprising the aminophosphonate hydrochloride) is separated by settling and is subjected to a basic treatment.
This acidic aqueous phase is preferably treated with an aqueous solution of an alkali metal carbonate or hydrogencarbonate, such as K2CO3, NaHCO3, KHCO3 or Na2CO3, or with an ammonia solution.
A second extraction (stage d)) of the released aminophosphonate (II) is subsequently carried out with the same solvent used in stage c).
The organic phase is advantageously washed with pure water and then concentrated under reduced pressure.
A virtually pure aminophosphonate (II) is obtained.
The oxidation of the aminophosphonate (II) to the nitroxide (I) is carried out according to stages a1) to c1) as described above.
Mention will be made, by way of illustration of organic solvents which can be used according to the present invention in stages a1) to c1), of aliphatic hydrocarbons, such as pentane, heptane or cyclohexane;
chlorinated solvents, such as CH2Cl2; esters of aliphatic acids, such as ethyl acetate or ethyl propionate, or a mixture of at least two of the abovementioned solvents.
Mention will be made, by way of illustration of nonhalogenated organic peracids which can be used according to the present invention, of peracetic acid, perpropionic acid or perbutanoic acid.
The compounds (I) can be identified by elemental analysis, HPLC, IR and EPR.
The compounds (II) obtained according to the invention can be identified by proton, 13C and 31P NMR, by IR and by elemental analysis.
The compounds obtained according to the process of the present invention have a sufficient purity to be used as regulators of radical polymerizations.
The process according to the present invention exhibits the advantage of resulting in high yields of xcex2-phosphorated nitroxide radicals.